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系統識別號 U0026-2308201218511000
論文名稱(中文) 探討SLIT2-Cdc42-Paxillin路徑在食道鱗狀上皮細胞癌發生變異之研究
論文名稱(英文) Deregulation of SLIT2-Cdc42-Paxillin Pathway in Esophageal Squamous Cell Carcinoma
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 100
學期 2
出版年 101
研究生(中文) 陳政宏
研究生(英文) Jeng-Hung Chen
學號 s26994037
學位類別 碩士
語文別 英文
論文頁數 68頁
口試委員 指導教授-王憶卿
口試委員-賴吾為
口試委員-呂佩融
口試委員-曾若嘉
中文關鍵字 食道癌  癌症轉移  SLIT2  Cdc42 
英文關鍵字 esophageal cancer  cancer metastasis  SLIT2  Cdc42 
學科別分類
中文摘要 研究背景: SLIT2為分泌型蛋白且屬於SLIT家族成員,過去發現在神經系統中,透過促進SLIT-ROBO1-srGAPs的訊息傳遞而使Cdc42不活化,進而調控神經細胞的遷移。本研究室先前在肺癌的研究發現SLIT2低表現與病人預後 (prognosis) 較差有關,然而SLIT2在食道鱗狀上皮細胞癌的角色尚未被研究探討。
研究目的: 本篇研究藉由人類食道上皮細胞癌細胞、動物以及臨床模式,探討SLIT2致癌機制為何。
研究方法與結果: 臨床研究中,使用IHC (immunohistochemistry) 偵測病人SLIT2蛋白表現,發現有35.3% (55/156) 的食道鱗狀上皮細胞癌病人有低度表現甚至缺少的情形,且SLIT2蛋白質低度表現與血管淋巴轉移、嚴重的腫瘤侵犯、腫瘤轉移到淋巴結,以及較大的腫瘤具有顯著統計意義。接著我們進一步使用RT-qPCR (quantitative reverse-transcriptase PCR),發現有45.6% (31/68) 的病人其SLIT2 mRNA表現量低,且SLIT2 mRNA低度表現與血管淋巴轉移以及較大的腫瘤具有顯著統計意義。接著使用Methylation-specific PCR (MSP),發現44.2% (53/120) 的食道癌病人其SLIT2基因啟動子過度甲基化,SLIT2基因啟動子過度甲基化與SLIT2 mRNA 表現呈現顯著負相關 (P=0.024),此研究結果指出在食道鱗狀上皮細胞癌中SLIT2基因啟動子過度甲基化是導致SLIT2 mRNA低表達的原因之一;接著我們發現在癌症分期為1或2以及不具有腫瘤淋巴轉移的食道癌病人,如果該病患SLIT2蛋白低表現,其整體存活率 (overall survival) 較差以及腫瘤復發率 (disease-free survival) 較高。我們進一步在食道鱗狀上皮細胞癌中進行細胞實驗,發現在食道鱗狀上皮細胞癌細胞株CE81T利用siRNA來抑制SLIT2的表現會促進癌細胞的轉移,另外在CE48T細胞株進行穩定轉染SLIT2則會抑制細胞的轉移能力;此外抑制SLIT2的表現則會促進活化態的Cdc42表現量增加以及促進p-FAK和p-Paxillin分佈在ESCC的細胞膜上。接著我們以老鼠尾部靜脈注射抑制SLIT2表現的CE81T細胞株及其控制組來進行細胞轉移實驗,結果顯示注射抑制SLIT2表現的CE81T細胞株的老鼠組別,其肺葉相較於控制組在外觀上有明顯的腫瘤生成,而且將其肺葉進行H&E染色,也發現相較於控制組有較多的腫瘤生成,且其腫瘤表現較多的 p-FAK 與 p-Paxillin。
結論: 本研究為第一篇以細胞、動物以及臨床證據指出SLIT2低表達與食道鱗狀上皮細胞癌病人有較差的預後以及癌細胞的轉移相關,而SLIT2的轉移抑制作用可能是透過SLIT2-Cdc42-Paxillin傳遞路徑。
英文摘要 Background: SLIT2, a secreted protein that belongs to the SLIT family, has been found to increase SLIT-ROBO1-srGAPs transduction and to inactivate Cdc42 in neural system as a result to modulate neural cell migration. Our previous study showed that low expression of SLIT2 is associated with poor prognosis in lung cancer. However, the role of SLIT2 has not been investigated in tumorigenesis of esophageal squamous cell carcinoma (ESCC).
Purpose: This study aims to investigate the mechanism of SLIT2 in ESCC cell, animal and clinical models.
Methods and Results: In clinical studies, the immunohistochemistry (IHC) data indicated that 35.3% (55/156) of tumors showed absence or low expression of SLIT2 protein, especially significant in patients with angiolymphatic tumor invasion, aggressive tumor depth status, (T status), metastasis to regional lymph nodes (N Status) and bigger tumor size. The quantitative reverse-transcriptase PCR (RT-qPCR) data indicated that decreased or absent SLIT2 transcripts were found in 45.6% (31/68) of tumor tissues in comparing with normal tissues, especially significant in patients with angiolymphatic tumor invasion and bigger tumor size. Methylation-specific PCR (MSP) assay showed that 44.2% (53/120) of ESCC tumors exhibited promoter hypermethylation of SLIT2 gene. A significant inverse correlation between mRNA expression and promoter hypermethylation was found (P=0.024), suggesting that promoter hypermethylation is responsible for low mRNA expression of SLIT2 gene in ESCC. The patients with low expression of SLIT2 protein had poor overall survival and disease-free survival in patients with stage 1-2 and N0 disease. We further studied the role of SLIT2 in ESCC cell model. Silencing of SLIT2 gene by siRNA increased cell migration in CE81T cells, while stable overexpressing SLIT2 reduced cell migration in CE48T cells. In addition, silencing of SLIT2 induced Cdc42 activity and promoted p-FAK and p-Paxillin localization to ESCC cell membrane. Animal studies using experimental metastasis assay by SLIT2 knockdown CE81T cells in comparison to their control cells. The results demonstrated that the group of mice injected with SLIT2 knocked down CE81T showed obviously more tumor nodules in lung tissue than the control group. Lung tissues were sectioned for H&E and IHC staining examination and there were significantly more tumor nodules with higher p-FAK and p-Paxillin stains in SLIT2 knock down group than in control group.
Conclusions: Our clinical, cellular and animal results provide first evidence that low expression of SLIT2 correlates with poor prognosis and promotes migration in ESCC, which may be mediated through SLIT2-Cdc42-Paxillin pathway.
論文目次 CONTENTS
Introduction
I. The clinical significance of esophageal cancer in Taiwan
(a) The unique clinical and epidemiological characteristics of esophageal cancer in Taiwan 1
(b) Metastasis-related genes and signalings in Esophageal squamous cell carcinoma (ESCC) 2
II. Overview of SLIT2 signaling pathway and SLIT2 gene
(a) The characteristics of SLIT family and its effectors Robo family and srGAP family 3
(b) SLIT2 in neuronal migration 4
III. Alteration of SLIT2 signaling pathway in cancer
(a) Alterations of SLIT2 gene in cancers 5
(b) The role of SLIT2 in tumor suppressive mechanism in cancers 6
(c) SLIT2-cdc42-paxillin signaling pathway in cancers 7
Study Basis and Specific Aims 9
Materials and Methods
I. Clinical samples of ESCC patients 11
II. RNA extraction and quantitative reverse-transcriptase PCR
(RT-qPCR) assays 11
III. Methylation-specific PCR (MSP) and Quantitative Methylation-specific PCR (qMSP) 12

IV. Immunohistochemistry (IHC) assay 12
V. Cell lines and culture conditions 13
VI. Expression vectors, RNAi, and Transfection 13
VII. 5-aza-2’-deoxycitidine (5-aza-dC) treatment 14
VIII. Wound healing assay 14
IX. Transwell migration assay 15
X. Conditioned medium assay 15
XI. Western blot analysis 16
XII. Cdc42 activation assay 16
XIII. Immunofluorescence staining and confocal microscopic analysis 17
XIV. MTT assay 17
XV. Anti-tumor metastasis study in animal model 18
XVI. Statistical analysis 18
Results
I. In clinical model:
(a) SLIT2 protein and mRNA are frequently low expression in ESCC patients 20
(b) SLIT2 gene is frequently hypermethylated in ESCC patients 21
(c) A significant inverse correlation between DNA methylation level and mRNA expression level, and a positive correlation between
SLIT2 protein expression level and mRNA expression level 21
(d) Patients with SLIT2 protein low expression show poor prognosis 22


II. In cell model:
(a) SLIT2 is hypermethylated and SLIT2 mRNA are down-regulated
in ESCC cell lines 22
(b) SLIT2 expression negatively correlates with cell migration
in ESCC cells 23
(c) SLIT2 expression negatively correlates with Cdc42 activity
in ESCC cells 24
(d) SLIT2 expression negatively correlates with active membrane
form of p-FAK and p-Paxillin in ESCC cells 24

III. In animal model:
(a) SLIT2 knockdown accelerates tumor metastasis in vivo 25
(b) Migration signaling proteins are validated in metastasis xenograft 25
Discussion 26
References 31
Tables 37
Figures 48
Appendix tables and figures 64

TABLE CONTENTS
Table 1. The primers and oligos used in the current study 38
Table 2. The antibodies and their reaction conditions
used in the current study 39
Table 3. The cell lines and their characteristics used in the current study 40
Table 4. The plasmids and their characteristics used in the current study 42
Table 5. Overall ESCC patient demographics 43
Table 6. Alteration of SLIT2 protein expression level
in relation to clinicopathological parameters
in 156 ESCC patients 44
Table 7. Alteration of SLIT2 mRNA expression level in relation to clinicopathological parameters in 68 ESCC patients. 45
Table 8. Alteration of Robo1 protein expression level in relation to clinicopathological parameters in 56 ESCC patients 46
Table 9. Alteration of srGAP1 protein expression level in relation to clinicopathological parameters in 41 ESCC patients 47

FIGURE CONTENTS
Figure 1. SLIT2 protein and mRNA are low expressed
in ESCC patients 49
Figure 2. Methylation status and unmethylation status of SLIT2 gene by methylation-specific PCR in ESCC patients 51
Figure 3. Correlation of DNA methylation level, mRNA expression level and protein expression level in ESCC patients 52
Figure 4. ESCC Patients with low expressed SLIT2 protein have poor survival 53
Figure 5. Restoration of SLIT2 expression by treatment with demethylation reagent 5-aza-dC 54
Figure 6. The mRNA and protein expression level of SLIT2 in normal esophageal epithelial cell and ESCC cell lines 56
Figure 7. SLIT2 negative regulated cell migration ability in CE48T and CE81T ESCC cells 57
Figure 8. SLIT2 negative regulated Cdc42 activity in CE48T
and CE81T ESCC cells 58
Figure 9. SLIT2 negative regulated p-Paxillin and p-FAK localized on ESCC cell membrane 59
Figure 10. Knock down of SLIT2 promotes tumor metastasis in vivo 60
Figure 11. Tissue IHC for SLIT2, p-paxillin and p-FAK in vivo 61
Figure 12. SLIT2 expression in plasma of ESCC patients 62
Figure 13. SLIT2 knockdown in CE81T cell line or SLIT2 over expression in CE48T cell line do not change cell proliferation 63

APPENDIX CONTENTS

Table 1. Summary of metastasis-related genes and signaling in ESCC 65
Table 2. Summary of SLIT2 abnormalities in human cancers 66
Figure 1. Schematic representation of SLIT/ROBO/SRGAP proteins and their interaction domains 67
Figure 2. Model for SLIT-induced neuronal migration 68
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